Systemic lupus is an autoimmune disease that results in immune complex glomerulonephritis in NZB/W mice and humans. Our studies in mice and humans with lupus show that CD4+ natural killer (NK) T cells spontaneously interact with autologous B cells via the CD1d antigen presenting molecule on the BALB/c cell surface, and induce polyclonal activation of the B cells with secretion of IgM, IgG and IgG anti-dsDNA autoantibodies. Conventional CD4+ T cells (non-NK T cells) have little helper activity for antibody secretion. The goal of the proposed research is to elucidate the cellular and molecular mechanisms by which NK T cells promote lupus glomerulonephritis in mice and man by studying the immune cells in the spleen, blood, and diseased kidneys. We hypothesize that the glomerulonephritis and the associated interstitial nephritis with lymphocytic infiltrates is dependent upon NK T cells with abnormal secretion of IL-4, IFN-?, and IL-17, and abnormal interactions with B cells that coincide with the onset of lupus disease activity. We will test the hypothesis by studying abnormalities in NK T cells and B cell subsets purified by flow cytometry, and by performing multi-color immunohistopathology that will identify germinal center formation, juxtaposition and localization of T and B cell subsets, intracellular cytokine and antibody expression, and activation state of immune cells. We will compare these parameters in lupus prone mice with and without specific NK T cell blocking treatment that ameliorates glomerulonephritis, and in adoptive hosts that are given purified NK T cells and B cells from mice with active disease. These studies should provide important information about new molecular targets for the treatment of lupus glomerulonephritis in humans. PUBLIC HEALTH RELEVANCE: Lupus is an autoimmune disease in which autoantibodies form complexes with self antigens, and the complexes injure the kidney after deposition in the glomeruli that filter waste products from the blood. Autoantibodies are produced by B cells that are activated by a rare immune cell, the NK T cell. The proposed research studies the interactions between the NK T cells and B cells in the immune tissues and inflamed kidneys that cause autoantibody formation, and studies ways to inhibit the interactions and ameliorate the kidney disease